Li Shau-Hsuan, Li Chien-Feng, Sung Ming-Tse, Eng Hock-Liew, Hsiung Ching-Yeh, Huang Wen-Wei, Lin Ching-Nan, Yu Shih-Chen, Huang Hsuan-Ying
Division of Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung, Taiwan.
Mod Pathol. 2007 Apr;20(4):497-507. doi: 10.1038/modpathol.3800762. Epub 2007 Mar 2.
Despite improvement in surgical techniques, prognosis of gallbladder carcinoma remains poor. It is desirable to identify prognostic biomarkers to aid in the development of targeted therapeutic strategies. Two SCF(Skp2) ubiquitin ligase-related proteins, Skp2 and cyclin-dependent kinase subunit 1 (Cks1), are involved in post-transcriptional degradation of p27(Kip1) tumor suppressor, which inhibits both cdk2/cyclin E and cdk2/cyclin A complexes and thus prevents transition to the S phase. However, the prognostic utility of p27(Kip1)-interacting cell cycle regulators has not been systematically assessed in gallbladder carcinoma. Immunohistochemistry was performed for p27(Kip1), Skp2, Cks1, cyclin E, cyclin A, and Ki-67 in tissue microarrays of 62 gallbladder carcinomas with follow-up. The data were correlated with clinicopathological features and overall survival (OS). The cumulative OS rate for all 62 cases was 42.9% at 3 years. Aberrant labeling indices (LIs) of p27(Kip1) (<20%), cyclin E (>or=5%), cyclin A (>or=5%), Cks1 (>or=40%), and Skp2 (>or=10%) were identified in 29, 58, 66, 21, and 57% of gallbladder carcinomas, respectively. By log-rank tests, downregulation of p27(Kip1) (P=0.0319) and high LIs of Skp2 (P=0.0006), Cks1 (P=0.0460), cyclin E (P=0.0070), and Ki-67 (P=0.0037) were predictive of inferior OS. Furthermore, the combined expression status of Skp2 and Ki-67 robustly defined three prognostically different groups (P=0.0001). In multivariate comparison, Skp2 overexpression represented the strongest independent adverse prognosticator (P=0.004, risk ratio (RR): 5.538), followed by Ki-67 LI >or=50% (P=0.016, RR: 3.254) and American Joint Committee on Cancer stages II-IV (P=0.013, RR: 3.163). In conclusion, aberrations of p27(Kip1)-interacting cell cycle regulators are common in gallbladder carcinomas. Skp2 overexpression is highly representative of biological aggressiveness and independently associated with poor OS, suggesting that it is a promising novel target for therapeutic intervention in aggressive cases. The combined assessment of Skp2 and Ki-67 LIs effectively risk-stratifies gallbladder carcinomas with different prognosis, which is worth being prospectively validated in future study.
尽管手术技术有所改进，但胆囊癌的预后仍然很差。识别预后生物标志物以辅助制定靶向治疗策略是很有必要的。两种SCF（Skp2）泛素连接酶相关蛋白，即Skp2和细胞周期蛋白依赖性激酶亚基1（Cks1），参与p27（Kip1）肿瘤抑制因子的转录后降解，p27（Kip1）可抑制cdk2/细胞周期蛋白E和cdk2/细胞周期蛋白A复合物，从而阻止细胞进入S期。然而，p27（Kip1）相互作用的细胞周期调节因子在胆囊癌中的预后价值尚未得到系统评估。对62例有随访资料的胆囊癌组织芯片进行p27（Kip1）、Skp2、Cks1、细胞周期蛋白E、细胞周期蛋白A和Ki-67的免疫组织化学检测。将数据与临床病理特征及总生存期（OS）进行关联分析。62例患者3年的累积总生存率为42.9%。在29%、58%、66%、21%和57%的胆囊癌中分别检测到p27（Kip1）异常标记指数（LI）（<20%）、细胞周期蛋白E（≥5%）、细胞周期蛋白A（≥5%）、Cks1（≥40%）和Skp2（≥10%）。通过对数秩检验，p27（Kip1）下调（P=0.0319）以及Skp2（P=0.0006）、Cks1（P=0.0460）、细胞周期蛋白E（P=0.0070）和Ki-67（P=0.0037）的高LI可预测较差的OS。此外，Skp2和Ki-67的联合表达状态明确区分出三个预后不同的组（P=0.0001）。在多因素比较中，Skp2过表达是最强的独立不良预后因素（P=0.004，风险比（RR）：5.538），其次是Ki-67 LI≥50%（P=0.016，RR：3.254）和美国癌症联合委员会II-IV期（P=0.013，RR：3.163）。总之，p27（Kip1）相互作用的细胞周期调节因子异常在胆囊癌中很常见。Skp2过表达高度代表生物学侵袭性，并与不良OS独立相关，表明它是侵袭性病例治疗干预的一个有前景的新靶点。Skp2和Ki-67 LI的联合评估有效地对预后不同的胆囊癌进行了风险分层，值得在未来研究中进行前瞻性验证。
